Low levels of oxygen (O{2}), or hypoxia elicit profound adaptive effects on cellular metabolism macromolecular biosynthesis, proliferation, and gene expression. Most transcriptional responses to O{2} deprivation are regulated by hypoxia inducible factors (HIFs), a family of O{2} sensitive transcription factors that transactivate genes with hypoxia response elements (HREs) and their promoters are enhancers. Two highly related HIF proteins, HIF-1a, and HIF-2a regulate a large number of target genes that mediate hypoxic adaptations. Hypoxia also influences three critical pathways that coordinate intracellular metabolism growth, namely c-Myc, mTOR, and p53. Whereas HIF-1a and HIF-2a frequently regulate overlapping responses to O{2} starvation, they exhibit opposing roles in c-Myc, mTOR, and p53 regulation. We hypothesize that overlap between the HIFs and these three pathways is important to cancer cell adaptation to oxygen and nutrient withdraw. To enhance our understanding of cancer cell metabolic adaptations, we propose to: (1) define how HIF-1a and HIF-2a differentially impact c-Myc and metabolism in renal carcinoma cells, (2) characterize HIF-1a versus HIF-2a modulation of the mTOR pathway and renal carcinoma, and (3) determine if HIF-2a regulation of p53 promotes renal carcinoma progression and resistance to therapy. Cells within solid tumors frequently encounter O{2} deprivation given the poor vascular function of tumor blood vessels. The ultimate goal of this proposal is to better define hypoxic regulation of cancer cell metabolism and develop novel therapies designed to combat the unique metabolism and physiology of these lesions.